The Ys and wherefores of protein kinase autoinhibition
The Ys and wherefores of protein kinase autoinhibition
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DOI：
10.1016/j.bbapap.2015.04.025
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发表时间：
2015-10-01
影响因子：
3.2
通讯作者：
Yeoh, Sharon
中科院分区：
文献类型：
--
作者：
Bayliss, Richard;Haq, Tamanna;Yeoh, Sharon
蛋白质磷酸化是调节细胞事件的关键反应，并由人类中超过500种蛋白激酶催化。蛋白激酶的活性通过一系列不同的机制受到严格控制。结构研究表明，激酶在其活性状态下所采用的构象是高度相似的，而非活性激酶可以采用多种构象。许多激酶通过自身抑制而保持在催化失活状态。这涉及激酶活性位点的构象，其不能支持催化并且需要通过信号（例如调节蛋白的结合）激活。在这篇综述中，我们简要地总结了一些成熟的自抑制机制，然后集中在一个相对未开发的模式的自抑制，首先发现在Nek家族的激酶，也是相关的IRE 1。这涉及阻断活性位点的酪氨酸侧链，并且必须经历构象变化才能具有激酶活性。我们称之为Tyr-down autopolyoty机制。我们总结了这种机制的证据，并描述了它在激酶抑制剂设计中的作用。最后，我们调查激酶组，以确定其他激酶的潜力，由一个自抑制酪氨酸下降机制。这篇文章是题为：蛋白激酶抑制剂的特刊的一部分。(C)2015 Elsevier B. V.版权所有。
Protein phosphorylation is a key reaction in the regulation of cellular events and is catalysed by over 500 protein kinases in humans. The activities of protein kinases are strictly controlled through a diverse set of mechanisms. Structural studies have shown that the conformation adopted by kinases in their active state is highly similar, whereas inactive kinases can adopt a variety of conformations. Many kinases are maintained in a catalytically inactive state through autoinhibition. This involves a conformation of the kinase active site that is unable to support catalysis and requires activation through a signal such as binding of a regulatory protein. In this review, we briefly summarise some of the well-established autoinhibitoiy mechanisms and then focus on a relatively unexplored mode of autoinhibition that was first discovered in the Nek family of kinases and is also relevant to IRE1. This involves a tyrosine side-chain that blocks the active site and which must undergo a conformational change to enable kinase activity. We have termed this the Tyr-down autoinhibitoty mechanism. We summarise the evidence for this mechanism and describe its role in kinase inhibitor design. Finally, we survey the kinome to identify other kinases with the potential to be governed by an autoinhibitory Tyr-down mechanism. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. (C) 2015 Elsevier B.V. All rights reserved.